Project Summary Apolipoprotein ?4 (APOE4) allele is the strongest genetic risk factor for Alzheimer?s disease (AD). Neuroimaging studies in humans have shown that cognitively normal APOE4 carriers develop vascular, metabolic and structural deficits decades before the aggregation of beta-amyloid (A?) and neurofibrillary tau tangles. Interventions that can restore these deficits to normal would be critical to potentially prevent the development of AD related neuropathology and cognitive impairment. The rationale of the study is to use the state-of-the-art, in vivo MRI methods to identify a potential intervention, Rapamcyin, for AD prevention in a mouse model that overexpresses human A? via 5 familial-AD mutations, and expresses human APOE4 (E4FAD). The central hypothesis is that multi-modal MRI can be used as surrogate markers to assess efficacy of Rapamycin for restoring brain vascular, metabolic, and structural functions in mice that carry APOE4 genes. We will also validate our MRI results by comparison with biochemical assays, and finally compare with behavioral outcomes. The hypothesis will be tested by pursuing three specific aims: 1) Test the hypothesis that Rapamycin restores neurovascular functions; 2) Test the hypothesis that Rapamycin protects neurometabolic functions; and, 3) Test the hypothesis that Rapamycin preserves structural and cognitive functions. The project is innovative because it employs cutting-edge, multi-disciplinary novel technology to focus on early interventions that may become an effective way to prevent AD-induced dementia for APOE4 carriers. The project is significant because with validation, these multimodal MRI methods will dramatically enhance future research for identifying potential therapeutics using animal models in the fields related to AD and other age- related neurodegenerative disorders. We can also translate our approach to future human studies because all the MRI methods used in the proposal are readily able to be used in humans. Because Rapamycin is FDA- approved, the findings from the study will also provide valuable information, and may pave a way, for future Rapamycin clinical trials to prevent dementia for pre-symptomatic APOE4 carriers. !